Thomas Benzing / Matthias Hackl - C 2

The role of slit diaphragm signalling of podocytes

Abstract

Chronic kidney disease (CKD) is becoming an increasingly prevalent condition affecting almost 10% of the population in the Western societies. The majority of kidney diseases that progress to CKD start in the glomerulus, the renal filtration unit, as a consequence of a limited capacity of glomeruli for regeneration and the limited ability of terminally differentiated glomerular podocytes for self-renewal 1. Podocytes enwrap the glomerular capillaries and elaborate primary and interdigitating secondary extensions that are connected by a membrane like cell junction, called the slit diaphragm 2. Over the past decade we showed that proteins residing at the slit diaphragm form an evolutionarily conserved mechanosensitive multiprotein complex that controls podocyte viability and function. Studies in C. elegans revealed a role for lipid-protein interactions at the slit diaphragm complex in mechanosensation and identified new components of the megadalton lipid-protein supercomplex at the filtration slit 3. These studies initiated new spurt of research worldwide that profoundly changed our view of glomerular filtration, the regulation of kidney function and our understanding of renal disease. However, most of these studies were based on cell culture experiments and the model organisms C. elegans and Drosophila as podocyte signalling dynamics could not be studied in living mice. Over the past three years we have now generated new approaches to functionally characterize proteome and phosphoproteome changes 4-7 as well as illuminate the signalling dynamics in living animals 8-10. Several essential questions can now be addressed. Here we focus on three unsolved questions in this new field of podocyte research:
(1) How does cGMP signalling affect intracellular calcium dynamics in podocytes? (2) How do intracellular cGMP and calcium levels change in podocytes stimulated with angiotensin II and purinergic activation? (3) Do alterations in cGMP and calcium affect glomerular circulation, permeation and convective flow and how does this change in podocyte disease models? We believe that this project will pave the way into a new era of podocyte research and ultimately help develop therapeutic interventions in a very important group of human disorders.

Clinical/medical relevance and sustainability in disease understanding

Over the past decade we have pioneered the concept of slit diaphragm signalling and showed that podocyte viability and function is critically controlled through proteins that were initially thought to only serve as part of a filtration barrier. This project embarks on our previous work to develop innovative strategies and novel tools to study podocyte signalling in vivo by combining functional proteomics and multiphoton imaging technologies in genetically engineered animals. We are convinced that the proposed experiments will help clarify the contribution of alterations of podocyte dynamics to CKD and enable us to attract additional new third-party funding as a result of the development of these novel tools for podocyte research.


Prof. Dr. med. Thomas Benzing

Chair CMMC

Prof. Dr. med. Thomas Benzing

Dept. II of Internal Medicine
Principal Investigator C 2

cmmc-office@uni-koeln.de

Work +49 221 478 89536

Fax (Work) +49 221 478 4833

CMMC Research Building
Robert-Koch-Str. 21
50931 Cologne

https://cmmc.uni-koeln.de

Publications - Thomas Benzing

Link to PubMed


Dr. med. Matthias Hackl

Dept. II of Internal Medicine

Dr. med. Matthias Hackl

Co-Principal Investigator C 2

matthias.hackl@uk-koeln.de

Publications - Matthias Hackl

Link to PubMed